Intervening up-regulated SLC7A5 could mitigate inflammatory mediator by mTOR-P70S6K signal in rheumatoid arthritis synoviocytes.

Abstract Objective: The disruption of metabolic events and changes to nutrient and oxygen availability due to sustained inflammation in RA increases the demand of bioenergetic and biosynthetic processes within the damaged tissue. The current study aimed to understand the molecular mechanisms of SLC7A5 (amino acid transporter) in synoviocytes of RA patients.Methods: Synovial tissues were obtained from OA and RA patients. Fibroblast-like synoviocytes (FLS) were isolated and SLC7A5 expression was examined by using RT-qPCR, immunofluorescence and Western blotting. RNAi and antibody blocking treatments were used to knockdown SLC7A5 expression or to block its transporter activities. mTOR activity assay and MMPs expression levels were monitored in RA FLS under amino acid deprivation or nutrient rich conditions. Results: RA FLS displayed significantly upregulated expression of SLC7A5 compared to OA FLS. Cytokine IL-1β was found to play a crucial role in up-regulating SLC7A5 expression via NF-κB pathway. Intervening SLC7A5 expression with RNAi or blocking its function by monoclonal antibody ameliorated MMP3 and MMP13 protein expression. Conversely, up regulation of SLC7A5 or tryptophan supplementation enhanced mTOR-P70S6K signals which promoted the protein translation of MMP3 and MMP13 in RA FLS.Conclusion: Activated NF-κB pathway up-regulates SLC7A5, which enhances mTOR-P70S6K activity and MMP3 and MMP13 expression in RA FLS.